尼莫地平自乳化软胶囊的研究
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摘要
尼莫地平(Nimodipine，NM)自乳化系统是以NM为主药，以油、乳化剂及助乳化剂等为辅料形成的热力学稳定的NM自乳化药物传递系统。将NM自乳化药物传递系统制成软胶囊，即得NM自乳化软胶囊(NMSEDDS soft capsule，NMSESC)。NM是第二代二氢吡啶类钙通道阻滞剂，临床多用于治疗脑出血，脑梗死，轻、中度高血压等。药动学实验表明，NM口服后胃肠道吸收迅速，但有严重的肝脏首过效应，因此血浆浓度低，生物利用度为5-13％，个体间差异很大。本文以自乳化系统为载体，将其制成软胶囊，可提NM的溶出，促进其吸收，提高口服生物利用度。
研究结果表明：25℃时NM在亚油酸乙酯中的平衡溶解度较其它油中大；NM在正辛醇／水体系的表观油水分配系数(P_(app))为17.78，亲脂性较好；同时建立了两种体外分析方法—紫外分光光度法和高效液相色谱法，其中高效液相色谱法可用于含有油和乳化剂等辅料时NM的含量测定。
选用亚油酸乙酯为油相，分别与不同的乳化剂和助溶剂进行配伍试验，以自乳化时间及成乳后乳液的稳定性等为指标考察自乳化情况，确定乳化剂为聚山梨酯80，助溶剂为Transcutol。在此基础上绘制体系的假三元相图，考察中发现药物的加入对自乳化区面积没有明显影响，确定了NM自乳化系统的最优处方。同时还考察了温度、搅拌速度、不同溶出介质和体积对自乳化性能的影响，并用总体液平衡反向透析法对NM自乳化胶囊的体外释药过程进行了初步考察。
对NMSESC的质量进行评价。结果动电电位为-20mV左右，NMSEDDS乳化后所得乳剂粒径在200nm左右，粒径分布较窄。含量、有关物质及累积释放度测定结果表明，各项指标均符合规定。NMSESC稳定性考察试验表明，制剂在强光照射下药物含量降低，有关物质增加，因此需避光保存；冷热循环试验、加速试验和留样试验表明，避光条件下NMSEDDS稳定性良好。
对NMSESC和市售胶囊、胶丸进行了Beagle犬体内药物动力学研究，结果表明：三者的达峰时间(T_(max))分别为0.799、0.815和1.099h，峰浓度(C_(max))分别为588.41、317.27和286.20ng·ml~(-1)，NMSESC相对于市售胶囊、胶丸的相对生物利用度分别为160.09％和139.13％。采用方差分析、双单侧t检验和(1-2α)置信区间法进行生物等效性评价，分析结果表明，NMSESC相对于市售胶囊、胶丸生物不等效。NMSESC更有利于NM的吸收。
测定小鼠灌胃给予NMSESC和市售胶囊、胶丸后，心、肝、脾、肺、肾、脑、血浆等组织中药物浓度的经时变化。经统计矩分析表明，NMSESC组中NM在血中的AUC和Cmax明显增大，提示NMSESC的相对生物利用度增大。NMSESC组与市售胶囊、胶丸组相比，小鼠肺、脑和心组织中药物分布明显提高，其中脑组织相对摄取率分别为1.60和1.29，提示NMSEDDS改变了药物在小鼠体内的分布，对血、肺、脑和心具有一定的靶向性。
Nimodipine Self-Emulsifying Drug Delivery System(NMSEDDS), choosing nimodipine as the main drug, oils and surfactants as vehicles, was a thermodynamically stable system. Nimodipine (NM), as one of the dihydropyridine calcium channel antagonists, has been used as an essential drug for the treatment of cerebral ischemia, vascular disease, angina pectoris and hypertension in clinic. Pharmacokinetics tests show that NM is well absorbed in the gastrointestinal tract after oral administration, but it is subject to extensive first-pass effect that results in very low plasma concentration, poor absolute bioavailability and significant inter-indiviual. Therefore, SEDDS was selected as the carrier to prepare NMSEDDS soft capsule (NMSESC) to increase dissolution, promote absorption and enhance bioavailability of NM.The solubilities of NM in Ethyl Linoleate was higher than other choosed oils. NM, the apparent partition coefficients in octanol/water was 17.78, was lipophilic. Two methods, UV spectrophotometry and HPLC, were developed for in vitro assay. HPLC could eliminate the disturbance of excipients on analysis.Ethyl Linoleate was selected for oil phase. Different surfactants and cosolvents were tested with Ethyl Linoleate, by means of investigating emulsifying time and the stability of the emulsion, Tween 80 was selected as surfactant and Transcutol as cosolvent. The pseudo-ternary phase diagrams was studied, the results show that NM had no apparent effect on the self-emulsifying region. We determined the optima formula for NMSEDDS, then investigate the affects of temperature, mill rate, different vehicle contents and volume on the self-emulsifying efficiency. We also studied the drug release by bulk- equilibrium reverse dialysis bag technique.The qualities of NMSESC were studied. Zeta potential was about -20 mV. The particle size was about 200 nm and the size distribution was narrow. We determined the content, the related substances and drug release of NMSESC, the results indicated they all meet the standard. The content was reduced in the highlight test, which show NM should kept under darkness. The stability of NMSESC was good in the cold-hot cycling test, accelerated test and long-term test under darkness.The pharmacokinetics of NMSESC was compared with commercial NM capsule and soft capsule in dogs. Their T_(max) were 0.799, 0.815 and 1.099 h, C_(max) were 588.41, 317.27 and 286.20 ng/ml respectively. The bioavailabilities of NMSESC was 160.09% and 139.13% compared with NM capsules and soft capsule. The results of variance analysis and two one side t-test showed that the absorption degree of NMSESC, NM capsule and soft capsule were unequal, SEDDS can promote the absorption of NM.
In this report, we also study the distribution of NM in mice and evaluate its targeting performance. After oral administration for NMSESC, commercial NM capsules and soft capsules, the concentration of NM in different tissues was determined by HPLC. The results showed that AUC and C_(max) of NM in plasma had been raised significantly, which indicate the relative bioavailability of NMSESC had been raised. In contrast with NM capsules and soft capsules group, the NM distribution in plung, brain and heart had been raised significantly in the NMSESC group. The relative tissue exposure to the brain is 1.60 and 1.26 respectively, which indicated that NMSEDDS could alter the NM distribution in mice and had the tendency of plasma, plung, brain and heart targeting in vivo.
研究结果表明：25℃时NM在亚油酸乙酯中的平衡溶解度较其它油中大；NM在正辛醇／水体系的表观油水分配系数(P_(app))为17.78，亲脂性较好；同时建立了两种体外分析方法—紫外分光光度法和高效液相色谱法，其中高效液相色谱法可用于含有油和乳化剂等辅料时NM的含量测定。
选用亚油酸乙酯为油相，分别与不同的乳化剂和助溶剂进行配伍试验，以自乳化时间及成乳后乳液的稳定性等为指标考察自乳化情况，确定乳化剂为聚山梨酯80，助溶剂为Transcutol。在此基础上绘制体系的假三元相图，考察中发现药物的加入对自乳化区面积没有明显影响，确定了NM自乳化系统的最优处方。同时还考察了温度、搅拌速度、不同溶出介质和体积对自乳化性能的影响，并用总体液平衡反向透析法对NM自乳化胶囊的体外释药过程进行了初步考察。
对NMSESC的质量进行评价。结果动电电位为-20mV左右，NMSEDDS乳化后所得乳剂粒径在200nm左右，粒径分布较窄。含量、有关物质及累积释放度测定结果表明，各项指标均符合规定。NMSESC稳定性考察试验表明，制剂在强光照射下药物含量降低，有关物质增加，因此需避光保存；冷热循环试验、加速试验和留样试验表明，避光条件下NMSEDDS稳定性良好。
对NMSESC和市售胶囊、胶丸进行了Beagle犬体内药物动力学研究，结果表明：三者的达峰时间(T_(max))分别为0.799、0.815和1.099h，峰浓度(C_(max))分别为588.41、317.27和286.20ng·ml~(-1)，NMSESC相对于市售胶囊、胶丸的相对生物利用度分别为160.09％和139.13％。采用方差分析、双单侧t检验和(1-2α)置信区间法进行生物等效性评价，分析结果表明，NMSESC相对于市售胶囊、胶丸生物不等效。NMSESC更有利于NM的吸收。
测定小鼠灌胃给予NMSESC和市售胶囊、胶丸后，心、肝、脾、肺、肾、脑、血浆等组织中药物浓度的经时变化。经统计矩分析表明，NMSESC组中NM在血中的AUC和Cmax明显增大，提示NMSESC的相对生物利用度增大。NMSESC组与市售胶囊、胶丸组相比，小鼠肺、脑和心组织中药物分布明显提高，其中脑组织相对摄取率分别为1.60和1.29，提示NMSEDDS改变了药物在小鼠体内的分布，对血、肺、脑和心具有一定的靶向性。
Nimodipine Self-Emulsifying Drug Delivery System(NMSEDDS), choosing nimodipine as the main drug, oils and surfactants as vehicles, was a thermodynamically stable system. Nimodipine (NM), as one of the dihydropyridine calcium channel antagonists, has been used as an essential drug for the treatment of cerebral ischemia, vascular disease, angina pectoris and hypertension in clinic. Pharmacokinetics tests show that NM is well absorbed in the gastrointestinal tract after oral administration, but it is subject to extensive first-pass effect that results in very low plasma concentration, poor absolute bioavailability and significant inter-indiviual. Therefore, SEDDS was selected as the carrier to prepare NMSEDDS soft capsule (NMSESC) to increase dissolution, promote absorption and enhance bioavailability of NM.The solubilities of NM in Ethyl Linoleate was higher than other choosed oils. NM, the apparent partition coefficients in octanol/water was 17.78, was lipophilic. Two methods, UV spectrophotometry and HPLC, were developed for in vitro assay. HPLC could eliminate the disturbance of excipients on analysis.Ethyl Linoleate was selected for oil phase. Different surfactants and cosolvents were tested with Ethyl Linoleate, by means of investigating emulsifying time and the stability of the emulsion, Tween 80 was selected as surfactant and Transcutol as cosolvent. The pseudo-ternary phase diagrams was studied, the results show that NM had no apparent effect on the self-emulsifying region. We determined the optima formula for NMSEDDS, then investigate the affects of temperature, mill rate, different vehicle contents and volume on the self-emulsifying efficiency. We also studied the drug release by bulk- equilibrium reverse dialysis bag technique.The qualities of NMSESC were studied. Zeta potential was about -20 mV. The particle size was about 200 nm and the size distribution was narrow. We determined the content, the related substances and drug release of NMSESC, the results indicated they all meet the standard. The content was reduced in the highlight test, which show NM should kept under darkness. The stability of NMSESC was good in the cold-hot cycling test, accelerated test and long-term test under darkness.The pharmacokinetics of NMSESC was compared with commercial NM capsule and soft capsule in dogs. Their T_(max) were 0.799, 0.815 and 1.099 h, C_(max) were 588.41, 317.27 and 286.20 ng/ml respectively. The bioavailabilities of NMSESC was 160.09% and 139.13% compared with NM capsules and soft capsule. The results of variance analysis and two one side t-test showed that the absorption degree of NMSESC, NM capsule and soft capsule were unequal, SEDDS can promote the absorption of NM.
In this report, we also study the distribution of NM in mice and evaluate its targeting performance. After oral administration for NMSESC, commercial NM capsules and soft capsules, the concentration of NM in different tissues was determined by HPLC. The results showed that AUC and C_(max) of NM in plasma had been raised significantly, which indicate the relative bioavailability of NMSESC had been raised. In contrast with NM capsules and soft capsules group, the NM distribution in plung, brain and heart had been raised significantly in the NMSESC group. The relative tissue exposure to the brain is 1.60 and 1.26 respectively, which indicated that NMSEDDS could alter the NM distribution in mice and had the tendency of plasma, plung, brain and heart targeting in vivo.
引文
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